1) Studies on cyclic GMP phosphodiesterase (PDE) in human, dog, cow and rat show that the enzyme is normally independent of calcium and calmodulin. In the retinas of Irish Setter dogs affected with rapid onset retinal degeneration, however, the PDE enzyme is calcium-dependent; also the PDE activity and the calmodulin concentration are abnormally low. Results obtained from intraocular injection of purified bovine brain calmodulin in affected Irish Setter dogs showed higher levels of PDE and calmodulin in some retinas injected with calmodulin than in the control retinas. 2) Biochemical studies of the intercellular fluids of the subretinal and subchoroidal spaces of the rabbit eye were also performed to begin to investigate possible enzyme activities in these important fluids. The subretinal fluid of the retinal fraction demonstrated high cyclic GMP PDE and calmodulin activities that did not appear to result from serum or tissue contamination.